The long range objective of this project is to develop a comprehensive view of the biochemical and pharmacological characteristics of substance P (SP) receptors and to ascertain their possible role in the pathogenesis of behavioral and/or extrapyramidal disorders. For this purpose we will take advantage of the diversity of functions that SP receptors subserve in different organs, the different types of cells in which they are located, the different innervation that they receive, and their specific pharmacological characteristics. In the brain, we will study the regional and subcellular distribution of SP receptors, their kinetic characteristics and their relationships with dopaminergic neurons. In the guinea-pig ileum longitudinal muscle we will study the different SP receptor types and the kinetic characteristics of the binding of labelled SP in relation to receptor desensitization and receptor alkylation. In the rat salivary glands we will study the kinetic characterization of the different receptor types and the effects of sympathectomy and decentralization on receptor number and affinity. We will also search for SP receptors in other tissues, but we are actually more interested in finding cells lines which might contain SP receptors, such as neuroblastoma x glioma NB108-15, pheochromocytoma PC12, neuroblastoma NB2a, etc. A SP receptor-containing cell line will provide a unique opportunity to study the intracellular biochemical events that mediate the effects of SP.